Iron complex compounds for theraputic use

ABSTRACT

The present invention relates to iron complex compounds for therapeutic use which are low in arsenic, chromium, lead, cadmium, mercury and/or aluminum, compositions thereof and processes for preparing said iron complex compounds.

FIELD OF THE INVENTION

The present invention relates to iron complex compounds for therapeuticuse which are low in arsenic, lead, chromium, mercury, cadmium and/oraluminum, compositions thereof and processes for preparing said ironcomplex compounds.

BACKGROUND OF THE INVENTION

The risks of iron deficiency and iron deficiency anemia are highlyrelevant for the health of humans and livestock worldwide.

Iron deficiency is associated with a number of common conditionsincluding pregnancy and lactation, childhood development,gastrointestinal bleeding, inflammatory bowel disease, congestive heartfailure, restless leg syndrome, parasitic infections, chronic ingestionof certain agents, impaired kidney function and numerous others. Ironproducts are commonly used to treat or prevent iron deficiency andanemia associated therewith in humans.

Prevention and treatment of iron deficiency is also an important aspectin livestock farming. For example, the use of injectable iron forprevention of iron deficiency anemia is nearly an industry standard inswine production throughout the world. Since initial reports in themid-twentieth century detailed a piglet's need for supplemental iron,200 mg doses of injectable iron have routinely been given to every pigas per product label directions (Kernkamp et al., J Anim Sci. 1962,21:527-532; Ullrey et al., J Anim Sci. 1959, 18:256-263; Zimmerman etal., J Anim Sci. 1959, 18:1409-1415). The administration of ironproducts to livestock is thus an established and often necessarypractice in livestock farming.

Various forms of iron products for use in the treatment or prevention ofiron deficiency and anemia associated therewith have been described.See, for example, WO 2016/206600 A1, WO 2016/066172 A1, WO 2010/108493A1, WO 99/48533 A1, U.S. Pat. No. 6,977,249 B1, EP 1 554 315 B1, U.S.Pat. No. 8,926,947 B2 and WO 2008/096130 A1, to name but a few.

It is an object of the present invention to provide iron products whichare safe for administration to humans and to livestock as well as forhuman consumers of food produced from livestock.

SUMMARY OF THE INVENTION

The inventors found that conventional iron products, in particular ironproducts for veterinary use, often contain relatively high amounts ofnon-iron metal impurities, such as arsenic, chromium, lead, mercury,cadmium or aluminum, which can be harmful to the health of humans and/ornon-human animals. Accumulation of such impurities over the food chainup to human consumers of livestock products may exacerbate this healthrisk. The inventors therefore devised a novel process for preparing ironcomplex compounds which are low in impurities such as arsenic, chromium,lead, mercury, cadmium and/or aluminum.

In one aspect, the present invention thus provides a process forpreparing an iron complex compound comprising the steps of

-   -   (i) providing an iron preparation comprising iron in a form        selected from a water-soluble iron salt, an iron hydroxide, an        iron oxide-hydroxide and a mixture of two or more thereof,        wherein        -   the amount of arsenic in the iron preparation does not            exceed 4.5 μg per g of iron, and        -   the amount of lead in the iron preparation does not exceed            1.5 μg per g of iron; and    -   (ii) contacting the iron preparation with a ligand in the        presence of water so as to form the iron complex compound.

In a further aspect, the present invention provides an iron complexcompound obtained by the process of the invention.

In a further aspect, the present invention provides an iron complexcompound, wherein

-   -   the amount of arsenic in the iron preparation does not exceed        4.5 μg per g of iron, and    -   the amount of lead in the iron preparation does not exceed 1.5        μg per g of iron.

In a further aspect, the present invention provides an iron complexcompound, wherein the amount of aluminum in the iron complex compounddoes not exceed 200 μg per g iron.

In a further aspect, the present invention provides a compositioncomprising the iron complex compound of the invention and apharmaceutically acceptable carrier.

In a further aspect, the present invention provides an iron complexcompound or composition of the invention for therapeutic use.

In a related aspect, the present invention provides an iron complexcompound or composition of the invention for use in treatment orprophylaxis of iron-deficiency in a subject.

The present invention also relates to the use of an iron complexcompound or composition of the invention in the manufacture of amedicament for treatment or prophylaxis of iron-deficiency in a subject.The present invention also relates a method for treatment or prophylaxisof iron-deficiency in a subject by administering an effective amount ofan iron complex compound or composition of the invention to the subject.

DETAILED DESCRIPTION OF THE INVENTION

Unless further specified, the term “iron complex compound” as usedherein refers to any complex of iron ions or iron particles comprisingFe³⁺ and/or Fe²⁺ and a ligand.

Expediently, the ligands and salts used in the iron complex compounds ofthe invention as well as the carriers and other ingredients of thecompositions thereof are physiologically acceptable. The term“physiologically acceptable” as used herein, means that the ligand,salt, carrier or other ingredient does not cause acute toxicity when atherapeutically effective amount of the iron complex compound or thecomposition comprising the ligand, salt, carrier or other ingredient isadministered to a subject.

Unless not further specified, the term “carbohydrate” as used hereinincludes carbohydrates which are reduced, oxidized, derivatized or acombination thereof as described herein. In particular, carbohydratescan be derivatized, for example, by the formation of ethers, amides,esters and amines with the hydroxyl groups of the carbohydrates or bythe conversion of aldehyde groups of the carbohydrates to glycolicgroups so as to form heptonic acids, for example dextran glucoheptonicacids or dextrin glucoheptonic acids, using a process as described,e.g., in U.S. Pat. No. 3,639,588. The term “carbohydrate” as used hereinis thus not limited to compounds having the empirical formulaC_(m)(H₂O)_(n), wherein m and n are integers which may be the same ordifferent from each other.

Carbohydrates which may be used as ligands in iron carbohydrate complexcompounds of the present invention include, for example,monosaccharides; disaccharides, e.g. sucrose and maltose;oligosaccharides and polysaccharides, e.g. maltodextrin, polyglucose,dextran, polymaltose and oligomaltose, polyisomaltose andoligoisomaltose; sugar alcohols, e.g. sorbitol and mannitol; sugar acidsand salts thereof, e.g. gluconic acid, gluconate, dextran glucoheptonicacid, dextrin glucoheptonic acid, dextran glucoheptonate and dextringlucoheptonate, as well as reduced and/or oxidized and/or derivatizedvariants thereof, e.g. carboxymaltose, polyglucose sorbitolcarboxymethyl ether, hydrogenated dextran, oxidized dextran,carboxyalkylated oligo- and polysaccharides, oxidized oligo- andpolysaccharides, hydrogenated dextrin, oxidized dextrin, hydrogenatedpolymaltose, hydrogenated oligomaltose, hydrogenated polyisomaltose,hydrogenated oligoisomaltose, hydrogenated oligomaltose, hydroxyethylstarch or a mixture of two or more thereof. In preferred embodiments,the carbohydrate is carboxymaltose, polyglucose sorbitol carboxymethylether, mannitol, dextran, hydrogenated dextran, sucrose, gluconate,dextrin, hydrogenated oligoisomaltose (oligoisomaltoside) or a mixtureof two or more thereof.

The term “oligosaccharide” as used herein refers to a carbohydrate, or areduced and/or oxidized and/or derivatized variant thereof, having asmall number, typically 3-10, monosaccharide units, or to a mixture oftwo or more carbohydrates, or reduced and/or oxidized and/or derivatizedvariants thereof, wherein the majority (e.g., at least 60%, at least70%, at least 80% or more) of the molecules have a small number,typically 3-10, monosaccharide units.

The term “monomer saccharide” as used herein refers to a monosaccharideor a reduced and/or oxidized and/or derivatized variant thereof, or to amixture of two or more monosaccharides and/or variants thereof.

The term “dimer saccharide” as used herein refers to a carbohydratehaving two monosaccharide units (such as a disaccharide) or a reducedand/or oxidized and/or derivatized variant thereof, or to a mixture oftwo or more carbohydrates, or reduced and/or oxidized and/or derivatizedvariants thereof, wherein the majority (e.g., at least 60%, at least70%, at least 80% or more) of the molecules have two monosaccharideunits.

Sugar alcohols are mono- or disaccharide derivatives wherein thealdehyde group is converted to a hydroxyl group.

Sugar acids are monosaccharide derivatives which carry a carboxyl group.The carboxyl group can be obtained by, for example, oxidizing thealdehyde group of an aldose so as to form an aldonic acid, oxidizing the1-hydroxyl group of a 2-ketose so as to form an α-ketoacid (ulosonicacid), oxidizing the terminal hydroxyl group of an aldose or ketose soas to obtain an uronic acid, or oxidizing both ends of an aldose so asto obtain an aldaric acid.

In step (i) of the process of the invention, an iron preparation isprovided that is low in arsenic and lead, and optionally is also low inchromium, mercury, cadmium and/or aluminum.

The amounts of said non-iron metals are indicated herein relative to theamount of iron in the iron preparation or iron complex compound. Metalssuch as iron, arsenic, chromium, lead, mercury, cadmium and aluminumexist in different forms (elemental form, salts, complex compounds). Theamounts of iron and non-iron metals such as arsenic, chromium, lead,mercury, cadmium and aluminum indicated herein refer to the total amountof the respective metal, regardless in which form it is present.

The amounts of non-iron metals are preferably determined usingInductively Coupled Plasma (ICP) methods such as Inductively coupledplasma mass spectrometry (ICP-MS). Examples of devices that can be usedfor this purpose include, but are not limited to, 8800 Triple QuadrupoleICP-MS (Agilent Technologies) and ICP-MS devices of the iCAP™ Q series(Thermo Fisher Scientific). Methods such as Atomic AbsorptionSpectroscopy (AAS) which have relatively high measurement limits and/orare sensitive to interference with iron are generally not recommended.

Unless specified differently, the term “about” as used herein in thecontext of a particular value indicates that the value can vary by up to20%, in particular up to 10% and more particularly up to 5%, e.g. up to1%.

In the iron preparation used in the process of the invention,

-   -   the amount of arsenic does not exceed 4.5 μg per g iron, for        example does not exceed 3.0 μg per g iron, 2.5 μg per g iron or        2.0 μg per g iron, and in particular does not exceed 1.5 μg per        g iron, for example does not exceed 1.0 μg per g iron, 0.8 μg        per g iron, 0.5 μg per g iron or 0.3 μg per g iron; and the        amount of lead does not exceed 1.5 μg per g iron, 1.3 μg per g        iron, 1.0 μg per g iron or 0.7 μg per g iron, and in particular        does not exceed 0.5 μg per g iron, for example does not exceed        0.4 μg per g iron or 0.2 μg per g iron; and    -   optionally, the amount of cadmium does not exceed 0.6 μg per g        iron, for example does not exceed 0.5 μg per g iron, and in        particular does not exceed 0.4 μg per g iron, for example does        not exceed 0.3 μg per g iron or 0.2 μg per g iron; and    -   optionally, the amount of mercury does not exceed 0.9 μg per g        iron, for example does not exceed 0.7 μg per g iron or 0.5 μg        per g iron, and in particular does not exceed 0.3 μg per g iron,        for example does not exceed 0.2 μg per g iron or 0.10 μg per g        iron; and    -   optionally, the amount of chromium does not exceed 330 μg per g        iron, for example does not exceed 250 μg per g iron or 170 μg        per g iron, and in particular does not exceed 100 μg per g iron,        example does not exceed 75 μg per g iron, 50 μg per g iron or 20        μg per g iron; and    -   optionally, the amount of aluminum does not exceed 200 μg per g        iron, for example does not exceed 150 μg per g iron, 100 μg per        g iron or 50 μg per g iron, and in particular does not exceed 25        μg per g iron, for example does not exceed 20 μg per g iron or        15 μg per g iron.

The iron preparation used in the process of the invention comprises ironin a form selected from a water-soluble iron salt, an iron hydroxide andan iron oxide-hydroxide. The iron preparation may contain a mixture oftwo or more of these iron forms.

In a particular embodiment, the iron preparation comprises awater-soluble iron salt, for example an iron bromide, sulfate orchloride, in particular ferric chloride (FeCl₃), ferrous chloride(FeCl₂) or a mixture thereof. Expediently, the water-soluble iron saltis a physiological acceptable salt.

In a further particular embodiment, the iron preparation comprises ironhydroxide, for example ferric hydroxide (Fe(OH)₃), ferrous hydroxide(Fe(OH)₂) or a mixture thereof.

In a further particular embodiment, the iron preparation comprises ironoxide-hydroxide. Iron oxide-hydroxides may also be termed ironoxy-hydroxides. Iron oxide-hydroxides are compounds which consist of oneor more than one iron ion, one or more than one oxo group, and one ormore than one hydroxyl group. Particular iron oxide-hydroxides include,e.g., ferric oxide-hydroxides which occur in anhydrous (FeO(OH)) formsand hydrated (FeO(OH).nH₂O) forms such as, e.g., ferric oxide-hydroxidemonohydrate (FeO(OH).H₂O). Iron oxide-hydroxides can be prepared forexample from aqueous iron(III) salt solutions by hydrolysis andprecipitation as described, e.g., in Rómpp lexicon Chemie, 10. Auflage,1997. Iron oxide-hydroxides can be present in different polymorphicforms. For example, polymorphs of FeO(OH) include α-FeO(OH) (goethite),β-FeO(OH) (akagnéite), γ-FeO(OH) (lepidocrocite) and δ-FeO(OH)(feroxyhyte).

The iron preparation used in the process of the present invention, i.e.an iron preparation that is low in non-iron metal impurities as requiredby the invention, can be obtained

-   -   (a) from iron pentacarbonyl; or    -   (b) by recrystallization of an iron salt from an aqueous        solution thereof; or    -   (c) by extracting an aqueous iron salt solution with an organic        solvent; or    -   (d) from iron precipitated at an anode during electrolysis of an        aqueous iron salt solution; or    -   (e) by contacting an aqueous iron salt solution with a base so        as to form a precipitate of iron hydroxide and separating the        precipitate from the liquid by filtration or centrifugation; or    -   (f) by distillation of ferric chloride from a mixture comprising        ferric chloride and non-volatile impurities.

According to a preferred embodiment, the iron preparation is obtained bya process wherein an aqueous iron salt solution (e.g., an aqueous ironsalt solution obtained during the processing of an iron-containingnickel ore for nickel production) is extracted with an organic solvent.

According to a particularly preferred embodiment, the iron preparationused in the process of the invention is prepared from ironpentacarbonyl.

The generation of an iron preparation as described herein:

-   -   (a) from iron pentacarbonyl, or    -   (b) by recrystallization of an iron salt from an aqueous        solution thereof, or    -   (c) by extracting an aqueous iron salt solution with an organic        solvent, or    -   (d) from iron precipitated at an anode during electrolysis of an        aqueous iron salt solution, or    -   (e) by contacting an aqueous iron salt solution with a base so        as to form a precipitate of iron hydroxide and separating the        precipitate from the liquid by filtration or centrifugation, or    -   (f) by distillation of ferric chloride from a mixture comprising        ferric chloride and non-volatile impurities        can, but is not required to, be a step of the process of the        present invention.

Methods for preparing a water-soluble iron salt, iron hydroxide or ironoxide-hydroxide from iron pentacarbonyl are known in the art. Forexample, in a first step, iron pentacarbonyl can be decomposed to formiron (so-called carbonyl iron) at an elevated temperature (e.g. 200° C.or more), optionally in the presence of a catalyst such as H₂, NO, PF₃,PH₃, NH₃ and/or I₂, as described for example in U.S. Pat. No. 4,056,386.The iron can be reacted with (preferably an excess of) hydrochloric acidso as to obtain FeCl₂. FeCl₂ can be reacted with hydrochloric acid and(preferably a slight deficit of) sodium chlorate so as to obtain FeCl₃.FeCl₂ can be reacted with hydrochloric acid and oxidized using, forexample, hydrogen peroxide so as to form FeCl₃. This reaction can beused to oxidize FeCl₂ remaining from the reaction with hydrochloric acidand sodium chlorate so as to achieve a more complete conversion of FeCl₂to FeCl₃. Also chlorine (Cl₂; gas) can be used as oxidation agent.

Carbonyl iron can be prepared, for example, by directing carbon monoxideonto hot iron (e.g., as hot as about 200° C.), preferably under highpressure (e.g., as high as 15-20 MPa). Such preparation of carbonyl ironis described, for example, in French patent application no. 607.134 ofBadische Anilin- & Soda-Fabrik published on Jun. 26, 1926.

Methods for preparing an iron preparation as described herein byrecrystallization of an iron salt preparation from an aqueous solutionthereof are known in the art. To this end, an aqueous solution of awater-soluble iron salt preparation is provided, the iron salt (e,g.,ferric nitrate) is recrystallized from the solution (e.g., by reducingthe temperature of the solution), the iron salt crystals are separatedfrom the liquid, are dissolved so as to form an aqueous solution thereofand then again subjected to recrystallization and separation. The stepsof dissolution, recrystallization and separation can be repeated for oneor several more times so as to increase the purity, and in particularreduce the amount of non-iron metal impurities, of the iron saltpreparation. According to a particular example, ferric nitrate isrecrystallized from an aqueous solution thereof containing nitric acid.Specifically, ferric nitrate is dissolved in about 55-65% aqueous nitricacid at about 50-60° C. The solution is cooled to about 15° C. or lowertemperature, where crystalline ferric nitrate precipitate is formed andcan be separated from the liquid. Said steps of dissolution,recrystallization and separation can be repeated for one or several moretimes.

Methods for preparing an iron preparation as described herein byextracting an aqueous iron salt solution with an organic solvent areknown in the art. To this end, an aqueous ferric chloride solution canbe treated with an organic solvent so as to selectively dissolve theferric chloride in the organic solvent (extraction), then theselectively dissolved ferric chloride can be recovered by stripping theorganic solvent from the ferric chloride.

Exemplary organic solvents include alcohols having about 4-20 carbonatoms, in particular alcohols having 6-10 carbon atoms, such asn-octanol, and organic solutions of amine salts such astri-n-laurylamine hydrochloride in toluene. The presence of hydrochloricacid in the aqueous ferric chloride solution can improve extractionefficiency. It is advantageous to increase the concentration of ferricchloride in the aqueous starting solution by partial evaporation beforeadding the organic solvent, in particular to a concentration in therange of 280-850 g/l ferric chloride. The purification cycle ofevaporation and solvent extraction can be repeated until the desiredpurity of the ferric chloride preparation is obtained. Aqueous solutionsof ferrous chloride can also be purified if the ferrous chloride isfirst converted to ferric chloride by oxidation with chlorine. Specificmethods for extraction of iron salts with organic solvents aredescribed, e.g., in CA 2318 823 A1 and Müller et al. (“Liquid-liquidextraction of ferric chloride by tri-n-laurylamine hydrochloride”, EUR2245.e, Euratom report, Transplutonium Elements Program, EuratomContract No. 003-61-2 TPUB, Presses Academiques Europeennes, Brussels,1965).

Methods for electrolysis of aqueous iron salt solutions wherein iron isprecipitated at an anode are known in the art. See, for example, Cain etal. (“Preparation of pure iron and iron-carbon alloy” in Bulletin of theBureau of Standards, Vol. 13, 1916) and Mostad et al. (Hydrometallurgy,2008, 90, 213-220). Suitable iron solutions for electrolysis includeiron chloride solutions, iron sulfate solutions and solutions containingboth iron chloride and iron sulfate. The solution is typically neutralor acidic.

An iron preparation as described herein can further be obtained bycontacting an aqueous iron salt solution with a base so as to form aprecipitate of iron hydroxide and separating the precipitate from theliquid by filtration or centrifugation. Suitable bases for precipitationof iron hydroxides include sodium hydroxide or sodium carbonate.Alternatively, sodium bicarbonate can be used. Methods for separatingsuch precipitate from the remaining solution by filtration orcentrifugation are known in the art.

An iron preparation that is low in non-iron metal impurities, such asthe iron preparation used in the process of the invention, can also beprepared by distillation of a mixture comprising ferric chloride andnon-volatile impurities. For distillation, the mixture is subjected to atemperature and a pressure which are chosen such that at the selectedpressure and temperature the mixture is at about its boiling point. Atthose conditions, the mixture separates into a vapor phase and a slurryof non-volatile impurities in liquid ferric chloride. The vapor issubstantially pure ferric chloride that can be recovered by separatingthe vapor from the slurry. According to particular embodiments, atemperature at about the boiling point of the mixture means atemperature that is within 10° C. of said boiling point and preferablyis at said boiling point. Distillation can be performed, e.g., at atemperature in the range of from 300° C. to 700° C. and a pressure inthe range of from 0.1 to 5.1 MPa, preferably in the range of from 0.2 to0.4 MPa, wherein at the selected pressure and temperature the mixture isat about its boiling point.

During distillation, settlement of non-volatile solids in the slurry canbe prevented by agitating the slurry mechanically (e.g., by paddlestirrer or the like) or, preferably, by bubbling a gas (e.g., nitrogen,helium, chlorine or a mixture thereof) through the slurry.

After separation of the ferric chloride vapor, the remaining slurry canbe recycled by heating the slurry so as to vaporize ferric chloride,separating and cooling the ferric chloride containing vapor andreintroducing it to the distillation process. Preferably, the recyclingof the slurry is performed such that the amount of solids present in theslurry during distillation is below about 20 wt-%, in particular belowabout 12 wt-%.

The mixture comprising ferric chloride and non-volatile impurities thatis introduced into the distillation process can be obtained, forexample, by chlorinating iron-containing ore (e.g., a titaniferous oresuch as ilmenite) so as to produce a gaseous mixture comprising ferricchloride and non-volatile impurities and cooling the gas so as toprecipitate a solid mixture of ferric chloride and non-volatileimpurities. Said solid mixture can then be introduced into thedistillation process. Prior to separating the solid mixture of ferricchloride and non-volatile impurities from the gaseous mixture, thegaseous mixture can optionally be subjected to a temperature above thedew-point of ferric chloride so as to remove non-volatile impuritieswhich are no longer gaseous at this temperature. The thus pre-purifiedgaseous mixture can then be cooled so as to precipitate a solid mixtureof ferric chloride and non-volatile impurities that can be introducedinto the distillation process. See, for example, U.S. Pat. no.3,906,077.

Different methods for preparing and purifying iron preparations can becombined so as to increase the purity of the iron preparation evenfurther. For example, iron prepared by electrolysis of an aqueous ironsalt solution can be converted into a water-soluble iron salt that isthen subjected to one or more cycles of

-   -   (1) dissolution so as to form an aqueous solution of the iron        salt,    -   (2) recrystallization of the iron salt from the aqueous solution        and    -   (3) separation of the recrystallized iron salt from the        remaining solution.

Iron complex compounds of the invention can be prepared by contacting aniron preparation that is low in arsenic and lead, and optionally is alsolow in chromium, mercury, cadmium and/or aluminum as described hereinwith a ligand in the presence of water. This represents step (ii) of theprocess for preparing an iron complex compound of the invention. Ironpreparations comprising iron in the form of an iron hydroxide and/oriron oxide-hydroxide can be used directly for this step. For example, aprecipitate of iron hydroxide (e.g., ferric hydroxide) and/or ironoxide-hydroxide in an aqueous solution is contacted with a ligand (e.g.,a carbohydrate preparation), followed by heating and raising the pH soas to form an iron complex compound (e.g., an iron complex compoundcomprising FeO(OH) cores). Alternatively, the iron hydroxide and/or ironoxide-hydroxide of the iron preparation is converted into awater-soluble iron salt as described herein by contacting the ironpreparation with an acid. Expediently this conversion is performed in anaqueous solution comprising the reactants (iron hydroxide and/or ironoxide-hydroxide and acid). The choice of the acid depends on the ironsalt to be produced. For example, iron chloride can be prepared byreacting the iron hydroxide and/or iron oxide-hydroxide of an ironpreparation with hydrochloric acid. The reagents which, in addition tothe iron preparation, are used in step (ii) of the process of theinvention for preparing the iron complex compound are expedientlysubstantially free of non-iron impurities such as arsenic, chromium,lead, mercury, cadmium and/or aluminum.

According to one group of embodiments, the iron complex compound is aniron carbohydrate complex compound, i.e. the ligand in the iron complexcompound is a carbohydrate.

Preferably, the content of reducing aldehyde groups in the carbohydrateis at least partially reduced. This can be achieved by hydrogenation,oxidation or a combination thereof. Iron carbohydrate complex compoundscomprising carbohydrates which are hydrogenated and/or oxidized can beprepared as described, for example, in U.S. Pat. No. 8,929,947 B2, EP 1554 315 B1, U.S. Pat. No. 6,977,249 B1, WO 2010/108493 A1 or WO 99/48533A1. The amount of reducing carbohydrate can be determined usingSomogyi's reagent.

Specifically, the aldehyde groups can be converted into hydroxyl groupsby hydrogenation, for example by reacting the carbohydrate with areducing agent, such as sodium borohydride in aqueous solution, or withhydrogen in the presence of a hydrogenation catalyst, such as Pt or Pd.

Alternatively or additionally to hydrogenation, the aldehyde groups canbe oxidized, for example by oxidation of the carbohydrate using anaqueous hypochlorite solution at a pH within the alkaline range, e.g.within the range of from pH 8 to pH 12, in particular from pH 9 to pH11. Suitable hypochlorites include, for example, alkali metalhypochlorites such as sodium hypochlorite. The aqueous hypochloritesolution can have a concentration of, for example, at least 13 wt-%, inparticular in the range of from 13 to 16 wt-%, calculated as activechlorine. The oxidation reaction can be performed at temperatures in therange of, for example, from 15 to 40° C., preferably from 25 to 35° C.Reaction times are, for example, in the range of from 10 min to 4 hours,such as from 1 to 1.5 hours. The addition of catalytic amounts ofbromine ions, e.g. in the form of alkali metal bromides such as sodiumbromide, can further the oxidation reaction but is not mandatory.

The aldehyde groups of the carbohydrate can be converted by bothhydrogenation and oxidation. This can be achieved, for example, in thatthe carbohydrate is first hydrogenated to convert part of the aldehydegroups into hydroxyl groups, and then substantially all of the remainingaldehyde groups are oxidized to carboxyl groups. Where the carbohydrateis a polysaccharide such as dextran, the average molecular weight of theiron carbohydrate complex formed therewith can be influenced byadjusting the ration of hydrogenated aldehyde groups to oxidizedaldehyde groups. To obtain a stable product, the amount of reducinggroups in the carbohydrate (e.g. dextran) before oxidation does notexceed 15 wt-%.

The carbohydrates, including reduced and/or oxidized carbohydrates, canbe derivatized by formation of, for example, ethers, amides, esters andamines with the hydroxyl groups of the carbohydrates. In a particularembodiment, the carbohydrate is derivatized by formation of carboxyalkylether, in particular carboxymethyl ether, with a hydroxyl group of thecarbohydrate. The use of carboxymethylated carbohydrate in a productsuch as an iron carbohydrate complex compound of the invention mayreduce the toxicity of the product when administered parenterally to asubject compared to a product comprising a correspondingnon-carboxylated carbohydrate.

Iron carbohydrate complex compounds of the present invention include,for example, iron carboxymaltose, iron polyglucose sorbitolcarboxymethyl ether complex, iron mannitol complex, iron dextran, ironhydrogenated dextran, iron oxidized dextran, iron carboxyalkylatedreduced oligo- and polysaccharides, iron sucrose, iron gluconate, irondextrin, iron hydrogenated dextrin, iron oxidized dextrin, ironpolymaltose, iron hydrogenated polymaltose, iron oligomaltose,hydrogenated iron oligomaltose, iron polyisomaltose, iron hydrogenatedpolyisomaltose, iron hydrogenated oligosaccharides such as ironhydrogenated oligoisomaltose, iron hydroxyethyl starch, iron sorbitol,iron dextran glucoheptonic acid (e.g., gleptoferron) and a mixture oftwo or more thereof. According to particular embodiments, the ironcarbohydrate complex compound of the present invention is selected fromiron carboxymaltose, iron polyglucose sorbitol carboxymethyl ethercomplex, iron mannitol complex, iron dextran, iron hydrogenated dextran,iron sucrose, iron gluconate, iron dextrin, iron hydrogenatedoligoisomaltose and a mixture of two or more thereof.

The carbohydrate in iron carbohydrate complex compounds of the inventiontypically has a weight average molecular weight (M_(W)) of from 500 to80,000 Da, such as from 800 to 40,000 Da or from 800 to 10,000 Da and inparticular from 800 to 3,000 Da.

The apparent molecular weight (M_(p)) of the iron carbohydrate complexcompounds of the invention is typically in the range of from 800 to800.000 Da, such as from 10,000 to 500,000 Da or from 20,000 to 400,000Da or from 50,000 to 300,000 Da and in particular from 90,000 to 200,000Da. The apparent molecular weight M_(r) can be determined bygel-permeation chromatography using, e.g., dextran standards. See, forexample, the method described in Jahn et al., Eur J Pharm Biopharm 2011,78, 480-491.

The amount of dimer in carbohydrate preparations which are (optionallyreduced and/or oxidized and/or derivatized) oligosaccharide orpolysaccharide preparations was found to be a key factor with regard tothe stability of the iron carbohydrate complex compounds preparedtherefrom. See WO 2010/108493 A1. In iron carbohydrate complex compoundsof the invention where the carbohydrate is an (optionally reduced and/oroxidized and/or derivatized) oligosaccharide or polysaccharidepreparation, the content of dimer saccharides in said preparation istherefore preferably 2.9 wt-% or less, in particular 2.5 wt-% or less,and especially 2.3 wt-% or less, based on the total weight of thecarbohydrate. It is also preferred that the content of monomersaccharide in the carbohydrate preparation is 0.5 wt-% or less, based onthe total weight of the carbohydrate. This reduces the risk of toxiceffects caused by free iron ions released from compounds of monomer andiron, especially when present in preparations for parenteraladministration. Low amounts of dimer saccharides and/or monomersaccharides as indicated above can be obtained, e.g., by removing saidsmaller saccharide molecules from a carbohydrate preparation by apurification method such as membrane filtration, for examples usingmembranes having cut-off values in the range of 340-800 Da. Theconcentration of dimer saccharides and monomer saccharides in thefractions obtained by the purification method can be monitored by gelpermeation chromatography. The content of (optionally reduced and/oroxidized and/or derivatized) oligosaccharide or polysaccharide in thefractions can be determined by optical rotation.

The amount of iron in the iron carbohydrate complex compound of theinvention, determined for dry matter, is typically in the range of from10 to 50 wt-%, such as from 15 to 45 wt-% and in particular from 24 to32 wt-%. The concentration of iron in iron complex solutions forinjection according to the invention is typically in the range of from25 to 300 mg/ml, such as from 50 to 200 mg/ml. In preferred particularembodiments of iron complex solutions for injection according to theinvention, the concentration of iron is about 100 mg/ml or about 200mg/ml.

In particular embodiments, the carbohydrate is a hydrogenatedpolysaccharide or hydrogenated oligosaccharide or mixture thereof(hereinafter referred to as hydrogenated poly-/oligosaccharide) having aweight average M_(W) of from 500 to 7,000 Da, such as from 500 to 3,000Da, from 700 to 1,400 Da and in particular of about 1,000 Da. The numberaverage molecular weight (M_(n)) of such hydrogenatedpoly-/oligosaccharide is preferably in the range of from 400 to 1,400Da, and 90 wt-% of these molecules have molecular weights of less than3,500 Da, in particular less than 2,700 Da, and the molecular weights ofthe remaining 10% of the molecules are below 4,500, in particular below3,200 Da. For example, said hydrogenated poly-/oligosaccharide is ahydrogenated polyglucose, oligoglucose or mixture thereof, such as ahydrogenated dextran, hydrogenated dextrin or hydrogenatedoligoisomaltose (oligoisomaltoside) or a mixture thereof, whereinhydrogenated oligoisomaltose, particularly hydrogenated oligoisomaltosewherein the majority (such as at least 60%, e.g. from 70 to 80%) of themolecules has 3-6 monosaccharide units, is preferred. Accordingly, inpreferred embodiments of the invention, the iron complex compound is aniron hydrogenated oligoisomaltose, in particular an iron(III)hydrogenated oligoisomaltose, wherein the majority (such as at least60%, e.g. from 70 to 80%) of the hydrogenated oligoisomaltosidemolecules has 3-6 monosaccharide units, such as iron(III) isomaltoside1000 (INN name: ferric derisomaltose). Iron isomaltosides are typicallycharacterized by a strong colloidal complex of iron oxide-hydroxide andhydrogenated isomaltose (isomaltoside) chains resulting in a gradualrelease of iron.

In the particular embodiments described above, the content of dimersaccharide of the hydrogenated poly-/oligosaccharide is preferably 2.9wt-% or less, in particular 2.5 wt-% or less, and especially 2.3 wt-% orless, based on the total weight of the hydrogenatedpoly-/oligosaccharide. Preferably, preparations of the hydrogenatedpoly-/oligosaccharide used for preparing iron carbohydrate complexcompounds of the invention have a content of monomer saccharide of 0.5wt-% or less. Iron hydrogenated dextran complex compounds prepared fromsuch hydrogenated poly-/oligosaccharide preparations typically have anapparent molecular weight (M_(p)) in the range of from 120,000 to180,000 Da, in particular from 130,000 to 160,000 Da. Before thehydrogenated poly-/oligosaccharide preparation is contacted with theiron preparation, the preparation can be purified by membrane processesso as to remove high molecular weight hydrogenated polysaccharidesand/or low molecular weight hydrogenated oligosaccharides. In particularembodiments, the hydrogenated poly-/oligosaccharide preparation has beenpurified by one or more membrane processes having a cut-off valuebetween 340 and 800 Da. In even more particular embodiments, thehydrogenated poly-/oligosaccharide preparation has been purified by oneor more membrane processes using a membrane having a cut-off value thatallows for holding back polysaccharides having a molecular weight above2,700 Da, optionally followed by further hydrolysis, and followed by oneor more membrane processes using a membrane having a cut-off valuebetween 340 and 800 Da.

In a particularly preferred embodiment, the iron complex compound of theinvention is a compound having the formula{FeO_((1-3X))(OH)_((1+3X))(C₆H₅O₇ ³⁻)_(X)},(C₆H₁₀O₆)_(R)(—C₆H₁₀O₅—)_(Z)(C₆H₁₃O₅)_(R) ₁ (MeCl)_(Y) that containsH₂O, wherein

X is 0.0311±0.0062, in particular of 0.0311±0.0031;

R is 0.1400±0.0420, in particular 0.1400±0.0210;

Z is 0.4900±0.1470, in particular 0.4900±0.0735;

Y is 1.8000±1.0800, in particular 1.8000±0.4500; and

Me is a monovalent metal ion such as a sodium ion or potassium ion, andis preferably a sodium ion.

In a further particularly preferred embodiment, the iron complexcompound of the invention is a compound having the formula{FeO_((1-3X))(OH)_((1+3X))(C₆H₅O₇ ³⁻)_(X)}, (H₂O)_(T),(C₆H₁₀O₆)_(R)(—C₆H₁₀O₅—)_(Z)(C₆H₁₃O₅)_(R), (MeCl)_(Y), wherein

X is 0.0311±0.0062, in particular 0.0311±0.0031;

T is 0.2500±0.1250, in particular 0.2500±0.24750;

R is 0.1400±0.0420, in particular 0.1400±0.0210;

Z is 0.4900±0.1470, in particular 0.4900±0.0735;

Y is 1.8000±1.0800, in particular 1.8000±0.4500; and

Me is a monovalent metal ion such as a sodium ion or potassium ion, andis preferably a sodium ion.

In particular embodiments, the iron complex compound of the invention isan iron complex with an poly-/oligosaccharide (e.g. a polyglucose suchas a dextran) that is both hydrogenated and oxidized as describedherein. Such iron complex compound typically has an apparent molecularweight (M_(p)) in the range of from 50,000 to 150,000 Da, in particularfrom 70,000 to 130,000 Da, more particularly 80,000 to 120,000 Da.

In particular embodiments, the iron complex compound of the invention isan iron complex where the carbohydrate is a hydrogenated dextran with aweight average molecular weight (M_(w)) in the range of from 2,000 to6,000 Da. In one of these particular embodiments, the iron complex hasan iron content (determined for dry matter) of from 36 to 41 wt-% and,optionally is present in the form of an injectable solution having aniron content of about 200 mg/ml. In another of these particularembodiments, the iron complex has an iron content (determined for drymatter) of from 23 to 39 wt-% and is optionally present in the form ofan injectable solution having about 100 mg/ml.

In another preferred embodiment, the iron complex is an iron dextrancomplex that complies with the British Pharmacopoeia and/or U.S.Pharmacopoeia monographs for Iron Dextran Injection.

Iron carbohydrate complex compounds of the invention can be prepared by

-   -   (1) providing an aqueous solution that comprises a carbohydrate        and an iron preparation as described herein comprising a        water-soluble iron salt (e.g. ferric chloride),    -   (2) adding a base to the aqueous solution so as to form iron        hydroxide, and    -   (3) then heating the aqueous solution so as to form the iron        carbohydrate complex compound.

Preferably, the pH of the aqueous solution in step (1) is acidic, e.g.the solution is at a pH of 2 or lower, so as to prevent theprecipitation of iron hydroxides. The addition of a base in step (2) ispreferably performed in a slow or gradual manner so as to increase thepH to, for example, a pH of 5 or more, such as up to pH 11, 12, 13 or14. Such gradual increase can be achieved by first adding a weak base(e.g., an alkali metal carbonate or alkaline earth metal carbonate suchas sodium carbonate, potassium carbonate, sodium bicarbonate orpotassium bicarbonate, or ammonia) to increase the pH, e.g., up to pH2-4, e.g., up to 2-3, and then further increasing the pH by adding astrong base (e.g., an alkali metal hydroxide or alkaline earth metalhydroxide such as sodium hydroxide, potassium hydroxide, calciumhydroxide or magnesium hydroxide).

Alternatively, iron carbohydrate complex compounds of the invention canbe prepared by

-   -   (1) providing an aqueous solution that comprises a carbohydrate        and an iron preparation as described herein comprising an iron        hydroxide, iron oxide-hydroxide or a mixture thereof, and    -   (2) then heating the aqueous solution so as to form the iron        carbohydrate complex compound.

The heating of the aqueous solution in the last step of the twoabove-described processes for preparing iron carbohydrate complexcompounds of the invention facilitates the formation of the ironcarbohydrate complex compound. For example, the aqueous solution may beheated to a temperature in the range of from 15° C. to boiling.Preferably, the temperature is gradually increased, for example in afirst step the aqueous solution is heated to a temperature of from 15 to70° C. and then is gradually heated further until boiling. To finalizethe reaction the pH can be reduced to, e.g., pH 5-6 by adding an acidsuch as, for example, HCl or aqueous hydrochloric acid. In oneembodiment, said reduction of pH is performed when the solution has beenheated to about 50° C. and before it is further heated.

After heating, the product can be further processed by filtration andits pH can be adjusted to a neutral or slightly acidic pH (e.g., pH 5 to7) by adding a base or acid such as those mentioned above. Furtheroptional steps include purification, in particular the removal of salts,which may be achieved by ultrafiltration or dialysis, and sterilizationwhich may be achieved by filtration and/or heat treatment (e.g., attemperatures of 121° C. or higher). The purified solution can be useddirectly for preparing pharmaceutical compositions. Alternatively, solidiron carbohydrate complex can be obtained by precipitation, e.g. byadding an alcohol such as ethanol, or by drying, e.g. spray-drying.

The iron carbohydrate complex compound can be stabilized by mixing itwith an organic hydroxyl acid or salt thereof such as citric acid, acitrate or a gluconate.

According to another group of embodiments, the iron complex compound isa polymeric ligand-substituted oxo-hydroxy iron complex compound.Polymeric ligand-substituted oxo-hydroxy iron complex compounds compriseor basically consist of iron ions (e.g., Fe³⁺), ligands and oxo and/orhydroxyl groups. The iron ions, oxo and/or hydroxyl groups form polyoxo-hydroxy iron particles. The ligands are incorporated therein throughsubstitution of part of the initially present oxo or hydroxyl groups.This substitution is generally non-stoichiometrical, occurs throughformal bonding and leads to distinct alterations in the chemistry,crystallinity and material properties of the oxo-hydroxy iron. Polymericligand-substituted oxo-hydroxy iron complex compounds are described, forexample, in WO 2008/096130 A1.

Suitable ligands for ligand-substituted oxo-hydroxy iron complexcompounds of the invention include, for example, carboxylic acids, suchas adipic acid, glutaric acid, tartaric acid, malic acid, succinic acid,aspartic acid, pimelic acid, citric acid, gluconic acid, lactic acid andbenzoic acid; food additives such as maltol, ethyl maltol and vanillin;

anions with ligand properties such as bicarbonate, sulphate andphosphate; mineral ligands such as silicate, borate, molybdate andselenate; amino acids, in particular proteinogenic amino acids, such astryptophan, glutamine, proline, valine and histidine; and nutrient-basedligands such as folate, ascorbate, pyridoxine and niacin; as well as amixtures of two or more thereof.

The average molar ratio of ligand to iron is typically in the range offrom 10:1 to 1:10, such as in the range of from 5:1 to 1:5, from 4.1 to1:4, from 3.1 to 1:3, from 2:1 to 1:2 or at about 1:1.

Polymeric ligand-substituted oxo-hydroxy iron complex compounds of theinvention can be prepared by contacting an iron preparation as describedherein that is low in arsenic and lead, and optionally is also low inchromium, mercury, cadmium and/or aluminum with a ligand in an aqueoussolution at a first pH(A) and then changing the pH(A) to a second pH(B)to cause a solid precipitation of the polymeric ligand-substitutedoxo-hydroxy iron complex compound. The solid precipitate can have aparticulate, colloidal or sub-colloidal (nanoparticulate) structure.

The pH(A) is different from the pH(B). Preferably, the pH(A) is moreacidic than the pH(B). For example, pH(A) is equal or below pH 2 andpH(B) is above pH 2. Starting from the pH at which oxo-hydroxypolymerization commences, the pH is preferably further increased tocomplete the reaction and promote precipitation of the polymericligand-substituted oxo-hydroxy iron complex compound formed. During saidpH change further ligands and/or excipients can be added. Said pH changeis preferably done in a gradual or stepwise manner, for example over aperiod of about 24 hours or over a period of about 1 hour, and inparticular over a period of 20 minutes. The pH change can be effected bythe addition of acids or bases. For example, the pH can be increased byadding sodium hydroxide, potassium hydroxide or sodium bicarbonate.

The polymeric ligand-substituted oxo-hydroxy iron complex compounds aretypically produced in aqueous solutions, wherein the concentrations ofiron ions and ligand are 1 μM or higher and in particular 1 mM orhigher. The ratio of iron ions and ligand is chosen such that therelative amount of iron ions is not too high such that the rate ofoxo-hydroxy polymerization occurs too rapidly and efficient ligandincorporation is prevented, and the relative amount of ligand is not toohigh to prevent iron oxo-hydroxy polymerization. For example, the ironconcentration is in the range of from 1 mM to 300 mM, such as from 20 mMto 200 mM and in particular at about 40 mM.

The ligands used for the formation of the polymeric ligand-substitutedoxo-hydroxy iron complex compounds may have some buffering capacitywhich helps to stabilizing the pH range during complex formation.Buffering can also be achieved by adding an inorganic or organicbuffering agent, which will not be involved in formal bonding with theiron ions, to the aqueous solution containing the iron preparation andthe ligand. Typically, the concentration of such buffer, if present, isless than 500 mM or less than 200 mM, and in particular less than 100mM.

The formation of the polymeric ligand-substituted oxo-hydroxy ironcomplex compounds typically takes place at a temperature within therange of from 20° C. to 120° C., e.g., 20° C. to 100° C., in particularfrom 20 to 30° C.

Optionally, the ionic strength in the aqueous solution comprising theiron preparation and the ligand can be increased by adding furtherelectrolyte such as, e.g., potassium chloride or sodium chloride in anamount of, e.g., up to 10 wt-%, such as up to 2 wt-%, and in particularup to 1 wt-%.

The solid precipitate of polymeric ligand-substituted oxo-hydroxy ironcomplex compound can be separated and optionally be dried and processedfurther by, e.g., grinding before further use or formulation.

The present invention also relates to iron complex compounds obtainableby a process of the invention as describe herein.

The present invention also relates to iron complex compounds, wherein

-   -   the amount of arsenic does not exceed 4.5 μg per g iron, for        example does not exceed 3.0 μg per g iron, 2.5 μg per g iron or        2.0 μg per g iron, and in particular does not exceed 1.5 μg per        g iron, for example does not exceed 1.0 μg per g iron, 0.8 μg        per g iron, 0.5 μg per g iron or 0.3 μg per g iron; and    -   the amount of lead does not exceed 1.5 μg per g iron, 1.3 μg per        g iron, 1.0 μg per g iron or 0.7 μg per g iron, and in        particular does not exceed 0.5 μg per g iron, for example does        not exceed 0.4 μg per g iron or 0.2 μg per g iron; and    -   optionally, the amount of cadmium does not exceed 0.6 μg per g        iron, for example does not exceed 0.5 μg per g iron, and in        particular does not exceed 0.4 μg per g iron, for example does        not exceed 0.3 μg per g iron or 0.2 μg per g iron; and    -   optionally, the amount of mercury does not exceed 0.9 μg per g        iron, for example does not exceed 0.7 μg per g iron or 0.5 μg        per g iron, and in particular does not exceed 0.3 μg per g iron,        for example does not exceed 0.2 μg per g iron or 0.10 μg per g        iron; and    -   optionally, the amount of chromium does not exceed 330 μg per g        iron, for example does not exceed 250 μg per g iron or 170 μg        per g iron, and in particular does not exceed 100 μg per g iron,        for example does not exceed 75 μg per g iron, 50 μg per g iron        or 20 μg per g iron; and    -   optionally, the amount of aluminum does not exceed 200 μg per g        iron, for example does not exceed 150 μg per g iron, 100 μg per        g iron or 50 μg per g iron, and in particular does not exceed 25        μg per g iron, for example does not exceed 20 μg per g iron or        15 μg per g iron.

In a 1^(st) embodiment, the iron complex compound of the invention ischaracterized in that

-   -   the amount of arsenic does not exceed 4.5 μg per g iron; and    -   the amount of lead does not exceed 1.5 μg per g iron; and    -   optionally, the amount of aluminum does not exceed 200 μg per g        iron, in particular does not exceed 150 μg per g iron and        preferably does not exceed 100 μg per g iron.

In a 2^(nd) embodiment, the iron complex compound of the invention ischaracterized in that

-   -   the amount of arsenic does not exceed 4.5 μg per g iron; and    -   the amount of lead does not exceed 1.5 μg per g iron; and    -   the amount of cadmium does not exceed 0.6 μg per g iron; and    -   the amount of mercury does not exceed 0.9 μg per g iron; and    -   optionally, the amount of aluminum does not exceed 200 μg per g        iron, in particular does not exceed 150 μg per g iron and        preferably does not exceed 100 μg per g iron.

In a 3^(rd) embodiment, the iron complex compound of the invention ischaracterized in that

-   -   the amount of arsenic does not exceed 4.5 μg per g iron; and    -   the amount of lead does not exceed 1.5 μg per g iron; and    -   the amount of cadmium does not exceed 0.6 μg per g iron; and    -   the amount of mercury does not exceed 0.9 μg per g iron; and    -   the amount of chromium does not exceed 330 μg per g iron; and    -   optionally, the amount of aluminum does not exceed 200 μg per g        iron, in particular does not exceed 150 μg per g iron and        preferably does not exceed 100 μg per g iron.

In a 4^(th) embodiment, the iron complex compound of the invention ischaracterized in that

-   -   the amount of arsenic does not exceed 1.5 μg per g iron; and    -   the amount of lead does not exceed 0.5 μg per g iron.

In a 5^(th) embodiment, the iron complex compound of the invention ischaracterized in that

-   -   the amount of arsenic does not exceed 1.5 μg per g iron; and    -   the amount of lead does not exceed 0.5 μg per g iron; and    -   the amount of cadmium does not exceed 0.4 μg per g iron; and    -   the amount of mercury does not exceed 0.3 μg per g iron.

In a 6^(th) embodiment, the iron complex compound of the invention ischaracterized in that

-   -   the amount of arsenic does not exceed 1.5 μg per g iron; and    -   the amount of lead does not exceed 0.5 μg per g iron; and    -   the amount of cadmium does not exceed 0.4 μg per g iron; and    -   the amount of mercury does not exceed 0.3 μg per g iron; and    -   the amount of chromium does not exceed 100 μg per g iron.

In a 7^(th) embodiment, the iron complex compound of the invention ischaracterized in that

-   -   the amount of arsenic does not exceed 1.5 μg per g iron; and    -   the amount of lead does not exceed 0.5 μg per g iron; and    -   the amount of cadmium does not exceed 0.4 μg per g iron; and    -   the amount of mercury does not exceed 0.3 μg per g iron; and    -   the amount of chromium does not exceed 100 μg per g iron; and    -   the amount of aluminum does not exceed 25 μg per g iron.

In a 8^(th) embodiment, the iron complex compound of the invention ischaracterized in that

-   -   the amount of arsenic does not exceed 1.5 μg per g iron; and    -   the amount of lead does not exceed 0.5 μg per g iron; and    -   the amount of cadmium does not exceed 0.4 μg per g iron; and    -   the amount of mercury does not exceed 0.3 μg per g iron; and    -   the amount of chromium does not exceed 100 μg per g iron; and    -   the amount of aluminum does not exceed 20 μg per g iron.

In a 9^(th) embodiment, the iron complex compound of the invention ischaracterized in that

-   -   the amount of arsenic does not exceed 1.5 μg per g iron; and    -   the amount of lead does not exceed 0.5 μg per g iron; and    -   the amount of cadmium does not exceed 0.4 μg per g iron; and    -   the amount of mercury does not exceed 0.3 μg per g iron; and    -   the amount of chromium does not exceed 100 μg per g iron; and    -   the amount of aluminum does not exceed 15 μg per g iron.

An iron complex compound according to any one of said 1^(st) to 9^(th)embodiments, or a composition thereof, can be used for treatment orprophylaxis of iron-deficiency in a subject. The subject may be a humansubject or a non-human animal, in particular a non-human mammal, e.g. apig, horse, dog, cat, camel, sheep, goat or cow. In case of iron complexcompounds according to any one of said 1^(st) to 3^(rd) embodiments, andcompositions thereof, the subject is preferably a human subject. In caseof iron complex compounds according to any one of said 4^(th) to 9^(th)embodiments, and compositions thereof, the subject is preferably aninfant of a non-human animal, in particular an animal for foodproduction (e.g., milk and/or meat production), such as a piglet.

An iron complex compound according to any one of said 1^(st) to 9^(th)embodiments can be formulated, and used, for various ways ofadministration, for example for intramuscular administration or forintravenous administration. Iron complex compounds according to any oneof said 1^(st) to 3^(rd) embodiments are preferably formulated, andused, for intravenous administration. Iron complex compounds accordingto any one of said 4^(th) to 9^(th) embodiments are preferablyformulated, and used, for intramuscular administration.

The present invention also relates to iron complex compounds, wherein

-   -   the amount of aluminum does not exceed 200 μg per g iron, for        example does not exceed 150 μg per g iron, 100 μg per g iron or        50 μg per g iron, and in particular does not exceed 25 μg per g        iron, for example does not exceed 20 μg per g iron or 15 μg per        g iron; and    -   optionally, the amount of arsenic does not exceed 4.5 μg per g        iron, for example does not exceed 3.0 μg per g iron, 2.5 μg per        g iron or 2.0 μg per g iron, and in particular does not exceed        1.5 μg per g iron, for example does not exceed 1.0 μg per g        iron, 0.8 μg per g iron, 0.5 μg per g iron or 0.3 μg per g iron;        and    -   optionally, the amount of lead does not exceed 1.5 μg per g        iron, 1.3 μg per g iron, 1.0 μg per g iron or 0.7 μg per g iron,        and in particular does not exceed 0.5 μg per g iron, for example        does not exceed 0.4 μg per g iron or 0.2 μg per g iron; and    -   optionally, the amount of cadmium does not exceed 0.6 μg per g        iron, for example does not exceed 0.5 μg per g iron, and in        particular does not exceed 0.4 μg per g iron, for example does        not exceed 0.3 μg per g iron or 0.2 μg per g iron; and    -   optionally, the amount of mercury does not exceed 0.9 μg per g        iron, for example does not exceed 0.7 μg per g iron or 0.5 μg        per g iron, and in particular does not exceed 0.3 μg per g iron,        for example does not exceed 0.2 μg per g iron or 0.10 μg per g        iron; and    -   optionally, the amount of chromium does not exceed 330 μg per g        iron, for example does not exceed 250 μg per g iron or 170 μg        per g iron, and in particular does not exceed 100 μg per g iron,        for example does not exceed 75 μg per g iron, 50 μg per g iron        or 20 μg per g iron.

In one embodiment, the iron complex compound of the invention ischaracterized in that

-   -   the amount of aluminum does not exceed 200 μg per g iron.

In a further embodiment, the iron complex compound of the invention ischaracterized in that

-   -   the amount of aluminum does not exceed 150 μg per g iron.

In a further embodiment, the iron complex compound of the invention ischaracterized in that

-   -   the amount of aluminum does not exceed 100 μg per g iron.

An iron complex compound according to any one of afore-mentioned threeembodiments, or a composition thereof, can be used for treatment orprophylaxis of iron-deficiency in a subject. The subject may be a humansubject or a non-human animal, in particular a non-human mammal, e.g. apig, horse, dog, cat, camel, sheep, goat or cow. Preferably, the subjectis a human subject.

An iron complex compound according to any one of afore-mentioned threeembodiments can be formulated, and used, for various ways ofadministration, for example for intramuscular administration or forintravenous administration.

The invention further provides compositions comprising an iron complexcompound of the invention as described herein and a pharmaceuticallyacceptable carrier. The form of the composition is chosen depending onthe intended mode of administration. The composition may therefore beadapted for oral, parenteral or other forms of administration.

Examples of compositions for oral use include granules, tablets,capsules (e.g., hard gelatin capsules or soft gelatin capsules) andliquid preparations such as solutions and suspensions. Tablets andcapsules can be prepared by conventional means using pharmaceuticallyacceptable carriers such as, e.g., pregelatinised maize starch,polyvinylpyrrolidone, hydroxypropyl methylcellulose, lactose,microcrystalline cellulose or calcium hydrogen phosphate, and furtherexcipients such as lubricants (e.g., magnesium stearate, talc, orsilica); disintegrants (e.g., potato starch or sodium starch glycolate);or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coatedusing methods well-known in the art. Liquid preparations for oraladministration may take the form of, e.g., solutions, syrups orsuspensions, or may be presented as a dry product for constitution withwater or other suitable liquid before use. Such liquid preparations canbe prepared by conventional means and include pharmaceuticallyacceptable additives such as suspending agents (e.g., sorbitol syrup,cellulose derivatives or hydrogenated edible fats); emulsifying agents(e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oilyesters, ethyl alcohol or fractionated vegetable oils); preservatives(e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid); buffersalts, flavoring, coloring agents and/or sweetening agents. Compositionsfor oral administration can be formulated for slow release, controlledrelease or sustained release of the iron complex compound.

Compositions for parenteral administration can have the form ofinjectable or infusible solutions, suspensions or emulsions in liquidcarriers such as, for example, sterile water, saline or other bufferedaqueous solutions. Such compositions may comprise further additives suchas stabilizing agents (e.g., citric acid, citrate or gluconate),antibacterial agents (e.g., benzyl alcohol or phenol), antioxidants(e.g., ascorbic acid or sodium bisulfite) and/or agents for adjustingtonicity (e.g., sodium chloride or dextrose). Alternatively, the ironcomplex compound may be presented in the form of a powder forconstitution with sterile water or saline or another suitable liquidbefore use. Compositions for parenteral administration may also beformulated as implantable or injectable depot compositions, for examplewith suitable polymeric or hydrophobic carriers.

In particular embodiments, the compositions of the invention areformulated for parenteral administration (e.g., intramuscular injection,subcutaneous injection, intravenous injection or intravenous infusion,optionally as bolus injection or infusion) such as, for example, asinjectable or infusible solutions in an aqueous carrier such as saline.

The compositions of the invention may comprise additional nutritional orpharmaceutical agents such as, e.g., vitamins, in particularwater-soluble vitamins, micronutrients such as, e.g., cobalt, copper,zinc or selenium, erythropoietin, bacteriostatic agents or antibiotics.Water-insoluble vitamins may be incorporated into aqueous compositionsof the invention by way of emulsification.

The invention provides iron complex compounds of the invention asdescribed herein for therapeutic use. Accordingly, methods foradministering an iron complex compound of the invention to a subject aredescribed herein. The iron complex compound can be administered, forexample, orally or parenterally (such as by intramuscular injection,subcutaneous injection, intravenous injection or intravenous infusion,optionally as bolus injection or infusion). The iron complex compoundcan be administered in the form of a composition thereof as describedherein.

In particular, iron complex compounds of the invention can be used forthe treatment or prophylaxis of iron-deficiency in a subject. Thesubject can be selected from, for example, pig, horse, dog, cat, camel,sheep, goat, cow and human.

The iron complex compounds of the invention are also useful for thetreatment or prophylaxis of iron-deficiency in infants such as, e.g.,children, piglets, foals, camel foals, lambs, goat kids or calfs.

The term infant as used herein includes non-adult offspring startingfrom neonates.

Iron deficiency that can be treated or prevented by administering aniron complex compound of the invention can be, for example, irondeficiency associated with chronic blood loss, acute blood loss,pregnancy, childbirth, lactation, childhood development, heavy uterinebleeding, menstruation, gastrointestinal bleeding, chronic internalbleeding, inflammatory bowel disease, congestive heart failure, restlessleg syndrome, parasitic infections, lost or impaired kidney functionsuch as due to chronic kidney disease or kidney failure, dialysis,surgery, chronic ingestion of agents such as alcohol, salicylates,steroids, non-steroidal anti-inflammatory agents, erythropoiesisstimulating agents (ESAs) or drugs inhibiting iron absorption.

The iron complex compounds of the invention are in particular useful forthe treatment or prophylaxis of iron-deficiency in a pregnant mammal, amammal expected to become pregnant (such as a mammal prior toinsemination) or a nursing mammal. It is recognized that the bloodhemoglobin level of mammals such as sows will decrease with increasingparity. According to particular embodiments, an iron complex compound ofthe invention is used for the treatment or prophylaxis ofiron-deficiency in a mammal of second or higher parity, such as thirdparity, such as forth parity, such as fifth parity, such as sixthparity, such as seventh parity, such as eighth parity or higher, that ispregnant or expected to become pregnant. The iron complex compounds ofthe invention can be administered to the mammal at one or more pointsbefore and/or during pregnancy, such as two, three, four, five, six ormore doses during pregnancy, e.g. over a period of 15 weeks to 2 weeksprior to delivery. The iron complex compounds can be administeredtogether with other nutritional or pharmaceutical agents such as, e.g.,vitamins, micronutrients such as, e.g., cobalt, copper, zinc orselenium, erythropoietin, bacteriostatic agents or antibiotics. Thetreatment or prophylaxis of iron deficiency in pregnant mammals ormammals expected to become pregnant using iron complex compounds of theinvention can decrease the rate of stillborn infants. The use of an ironcomplex compound of the invention for the treatment or prophylaxis ofiron deficiency in a pregnant mammal or a mammal expected to becomepregnant or a nursing mammal can increase the survival, health and/orgrowth of the offspring until weaning and can treat or prevent an irondeficiency in a fetus or infant to be born or nursed by said mammal.This includes the treatment or prevention of iron deficiency in thebrain of a fetus or infant. Iron deficiency in the brain of a fetus orinfant may cause abnormal development of the fetal or infant brain andis associated with diseases and disorders such as restless leg syndrome(RLS), attention deficit hyperactivity disorder (ADHD), attentiondeficit disorder (ADD), absence seizure, bipolar disorder,schizophrenia, obsessive-compulsive disorder (OCD), autism andborderline personality disorder (BPD). See WO 2016/206699 A1. An ironcomplex compound of the invention can therefore be used for treating orpreventing iron deficiency in a fetus or infant, in particular irondeficiency in the brain of a fetus or infant, by administering the ironcomplex compound to the mother of the fetus or infant or to the mammalnursing the infant, wherein the iron complex compound can beadministered to the mother during the phase prior to pregnancy and/orduring pregnancy and/or during nursing.

The iron complex compounds of the invention are also useful for thetreatment or prophylaxis of iron-deficiency in a human suffering fromlost or impaired kidney function, for example a human in need ofdialysis. Humans with lost or impaired kidney function are often low inerythropoietin and receive drugs such as ESAs to allow for sufficienterythrogenesis. Erythrogenesis induced by ESAs can use up the patient'siron reserves faster than normal, thus increasing the risk of irondeficiency. Moreover, the diet of human patients on dialysis may limitthe intake of certain iron-rich foods such as red meat and beans, andthus the ability of the patients to take up sufficient iron with theirdiet. Further, frequent blood sampling for laboratory testing, surgicalprocedures for vascular access as well as blood loss into thehemodialyzer and tubing are further factors which contribute to ironloss of the patients. Humans suffering from lost or impaired kidneyfunction, and especially humans in need of dialysis on dialysis, aretherefore at particular risk of iron-deficiency.

The amount of aluminum in the iron complex compound of the invention foradministration to a human subject, in particular a patient sufferingfrom lost or impaired kidney function, such as a patient in need ofdialysis, preferably does not exceed 200 μg per g of iron, for exampledoes not exceed 150 μg per g iron, 100 μg per g iron or 50 μg per giron, and in particular does not exceed 25 μg per g iron, 20 μg per giron or 15 μg per g iron.

The amount of aluminum in the iron complex compound of the invention foradministration to an infant of a non-human animal subject, in particularan infant of a non-human mammal, e.g. a piglet, preferably does notexceed 25 μg per g iron, for example does not exceed 20 μg per g iron or15 μg per g iron.

The iron complex compound of the invention is suitable for beingadministered to a subject at a dose containing 200 mg or more ironwithin 2 minutes or less.

A single dose of iron complex compound of the invention may contain 200mg iron or more, 500 mg iron or more, such as 750 mg iron or more, forexample 500 to 1000 mg iron.

The iron complex compound of the invention can be administered to asubject, such as a human, at an amount of up to 5 mg iron per kgbodyweight of the subject in one sitting, up to 10 mg iron per kgbodyweight of the subject in one sitting, up to 15 mg iron per kgbodyweight of the subject in one sitting or even up to 20 mg iron per kgbodyweight of the subject in one sitting, such as for example 15 to 20mg iron per kg bodyweight of the subject in one sitting.

The amount of iron complex compound of the invention that can beadministered to a subject such as a piglet can be even higher such as upto 50 mg iron per kg bodyweight in one sitting, up to 100 mg iron per kgbodyweight in one sitting or up to 200 mg iron per kg bodyweight in onesitting, for example about 200 mg iron per kg bodyweight of the subjectin one sitting.

The use of an iron complex compound of the invention for the treatmentor prophylaxis of iron deficiency may comprise administration of onedose of iron complex compound containing an amount of 200 mg or moreiron every four weeks or more frequently, for example every three weeksor more frequently, every two weeks or more frequently, or every week ormore frequently.

In addition to uses as therapeutic iron supplements, the iron complexcompounds of the invention can also be used, for example, as dietarymineral supplement or fortificant, anti-hematinic drug or iron basedphosphate binding agent. For said additional uses the iron complexcompound is usually administered orally.

The present invention further relates to the following embodiments E1 toE68.

E1. A process for preparing an iron complex compound comprising thesteps of

-   -   (i) providing an iron preparation comprising iron in a form        selected from a water-soluble iron salt, an iron hydroxide or an        iron oxide-hydroxide, wherein        -   the amount of arsenic in the iron preparation does not            exceed 4.5 μg per g of iron, and        -   the amount of lead in the iron preparation does not exceed            1.5 μg per g of iron; and    -   (ii) contacting the iron preparation with a ligand in the        presence of water so as to form the iron complex compound.

E2. The process of E2, wherein

-   -   the amount of cadmium in the iron preparation does not exceed        0.6 μg per g of iron, and    -   the amount of mercury in the iron preparation does not exceed        0.9 μg per g of iron.

E3. The process of E1 or E2, wherein

-   -   the amount of chromium in the iron preparation does not exceed        330 μg per g of iron.

E4. The process of any one of E1-E3, wherein the amount of aluminum inthe iron preparation does not exceed 200 μg per g of iron.

E5. The process of any one of E1-E4, wherein the iron preparation isobtained

-   -   (a) from iron pentacarbonyl; or    -   (b) by recrystallization of an iron salt from an aqueous        solution thereof; or    -   (c) by extracting an aqueous iron salt solution with an organic        solvent; or    -   (d) from iron precipitated at an anode during electrolysis of an        aqueous iron salt solution; or    -   (e) by contacting an aqueous iron salt solution with a base so        as to form a precipitate of iron hydroxide and separating the        precipitate from the liquid by filtration or centrifugation; or    -   (f) by distillation of ferric chloride from a mixture comprising        ferric chloride and non-volatile impurities.

E6. The process of E5, wherein the recrystallization of an iron saltfrom an aqueous solution thereof is the recrystallization of ferricnitrate from an aqueous solution containing nitric acid.

E7. The process of E5, wherein the iron salt is ferric chloride, and theorganic solvent is an alcohol having from 4 to 20 carbon atoms, inparticular from 6 to 10 carbon atoms, or an organic solution of an aminesalt.

E8. The process of E5, wherein the electrolysis of an aqueous iron saltsolution is the electrolysis of an aqueous solution comprising ironchloride or iron sulfate.

E9. The process of E5, wherein the base with which the aqueous iron saltsolution is contacted is selected from sodium hydroxide, sodiumbicarbonate and sodium carbonate.

E10. The process of any one of E1-E9, wherein the iron preparationcomprises a water-soluble iron salt that is obtained by converting aniron hydroxide, iron oxide-hydroxide or a mixture thereof to awater-soluble iron salt.

E11. The process of any one of E1-E10, wherein the iron complex compoundis an iron carbohydrate complex compound.

E12. The process of E11, wherein the content of reducing aldehyde groupsin the carbohydrate that serves as ligand in the iron complex compoundhas been reduced by

-   -   oxidation,    -   hydrogenation, or    -   a combination of both.

E13. The process of E11 or E12, wherein the iron preparation of step (i)comprises a water soluble iron salt and the step (ii) of the processcomprises

-   -   (1) providing an aqueous solution comprising the iron        preparation and a carbohydrate,    -   (2) adding a base to the aqueous solution so as to form iron        hydroxide, and    -   (3) then heating the aqueous solution so as to form the iron        carbohydrate complex compound.

E14. The process of E11 or E12, wherein the iron preparation of step (i)comprises an iron hydroxide or an iron oxide-hydroxide and the step (ii)of the process comprises:

-   -   (1) providing an aqueous solution comprising the iron        preparation and a carbohydrate, and    -   (2) then heating the aqueous solution so as to form the iron        carbohydrate complex compound.

E15. The process of any one of E11-E14, wherein the iron carbohydratecomplex compound is selected from iron carboxymaltose, iron polyglucosesorbitol carboxymethyl ether complex, iron mannitol complex, irondextran, iron hydrogenated dextran, iron oxidized dextran, ironcarboxyalkylated reduced oligo- and polysaccharides, iron sucrose, irongluconate, iron dextrin, iron hydrogenated dextrin, iron oxidizeddextrin, iron polymaltose, iron hydrogenated polymaltose, ironpolyisomaltose, iron hydrogenated polyisomaltose, iron hydrogenatedoligosaccharides such as iron hydrogenated oligoisomaltose, ironhydroxyethyl starch, iron sorbitol, iron dextran glucoheptonic acid anda mixture of two or more thereof.

E16. The process of any one of E11-E15, wherein the iron carbohydratecomplex compound is selected from iron carboxymaltose, iron polyglucosesorbitol carboxymethyl ether complex, iron mannitol complex, irondextran, iron hydrogenated dextran, iron sucrose, iron gluconate, irondextrin, iron hydrogenated oligoisomaltose and a mixture of two or morethereof.

E17. The process of any one of E11-E16, wherein the carbohydratecomponent of the iron carbohydrate complex compound has a weight averagemolecular weight (M_(W)) of from 500 to 80,000 Da.

E18. The process of any one of E11-E17, wherein the apparent molecularweight of the iron carbohydrate complex compound is in the range of from800 to 800.000 Da.

E19. The process of any one of E1-E10, wherein the iron complex compoundis a polymeric ligand-substituted oxo-hydroxy iron complex compound.

E20. The process of E19, wherein step (ii) of the process comprises

-   -   (1) contacting the iron preparation with the ligand in an        aqueous solution at a first pH(A); and    -   (2) changing the pH(A) to a second pH(B) to cause a solid        precipitation of the polymeric ligand-substituted oxo-hydroxy        iron complex compound.

E21. The process of E19 or E20, wherein the ligand is selected from acarboxylic acid, such as adipic acid, glutaric acid, tartaric acid,malic acid, succinic acid, aspartic acid, pimelic acid, citric acid,gluconic acid, lactic acid and benzoic acid; flavoring agents such asmaltol, ethyl maltol and vanillin; an anion with ligand properties suchas bicarbonate, sulphate and phosphate; a mineral ligand such assilicate, borate, molybdate and selenate; an amino acid such astryptophan, glutamine, proline, valine and histidine; and anutrient-based ligand such as folate, ascorbate, pyridoxine and niacin;and a mixture of two or more thereof.

E22. The process of any one of E19-E21, wherein the average molar ratioof ligand to iron is in the range of from 10:1 to 1:10.

E23. The process of any one of E1-E22, further comprising the step ofmixing the iron complex compound with a compound selected from citricacid, a citrate and a gluconate.

E24. An iron complex compound obtainable by the process of any one ofE1-E23.

E25. An iron complex compound, wherein

-   -   the amount of arsenic in the iron complex compound does not        exceed 4.5 μg per g iron, and    -   the amount of lead in the iron complex compound does not exceed        1.5 μg per g iron.

E26. The iron complex compound of E25, wherein

-   -   the amount of arsenic in the iron complex compound does not        exceed 1.5 μg per g of iron, and    -   the amount of lead in the iron complex compound does not exceed        0.5 μg per g of iron.

E27. The iron complex compound of E25 or E26, wherein

-   -   the amount of cadmium in the iron complex compound does not        exceed 0.6 μg per g of iron, and    -   the amount of mercury in the iron complex compound does not        exceed 0.9 μg per g of iron.

E28. The iron complex compound of E27, wherein

-   -   the amount of cadmium in the iron complex compound does not        exceed 0.4 μg per g of iron, and    -   the amount of mercury in the iron complex compound does not        exceed 0.3 μg per g of iron.

E29. The iron complex compound of any one of E25-E28, wherein

-   -   the amount of chromium in the iron complex compound does not        exceed 330 μg per g of iron.

E30. The iron complex compound of E29, wherein

-   -   the amount of chromium in the iron complex compound does not        exceed 100 μg per g of iron.

E31. The iron complex compound of any one of E25-E30, wherein

-   -   the amount of aluminum in the iron complex compound does not        exceed 200 μg per g of iron.

E32. The iron complex compound of E31, wherein the amount of aluminum inthe iron complex compound does not exceed 100 μg per g of iron.

E33. The iron complex compound of E32, wherein the amount of aluminum inthe iron complex compound does not exceed 25 μg per g of iron.

E34. An iron complex compound, wherein the amount of aluminum in theiron complex compound does not exceed 200 μg per g iron.

E35. The iron complex compound of E34, wherein the amount of aluminum inthe iron complex compound does not exceed 100 μg per g iron.

E36. The iron complex compound of E34, wherein the amount of aluminum inthe iron complex compound does not exceed 25 μg per g iron.

E37. The iron complex compound of any one of E34-E36, wherein

-   -   the amount of arsenic in the iron complex compound does not        exceed 4.5 μg per g iron, and    -   the amount of lead in the iron complex compound does not exceed        1.5 μg per g iron.

E38. The iron complex compound of E37, wherein

-   -   the amount of arsenic in the iron complex compound does not        exceed 1.5 μg per g of iron, and    -   the amount of lead in the iron complex compound does not exceed        0.5 μg per g of iron.

E39. The iron complex compound of any one of E34-E38, wherein

-   -   the amount of cadmium in the iron complex compound does not        exceed 0.6 μg per g of iron, and    -   the amount of mercury in the iron complex compound does not        exceed 0.9 μg per g of iron.

E40. The iron complex compound of E39, wherein

-   -   the amount of cadmium in the iron complex compound does not        exceed 0.4 μg per g of iron, and    -   the amount of mercury in the iron complex compound does not        exceed 0.3 μg per g of iron.

E41. The iron complex compound of any one of E34-E40, wherein

-   -   the amount of chromium in the iron complex compound does not        exceed 330 μg per g of iron.

E42. The iron complex compound of E41, wherein

-   -   the amount of chromium in the iron complex compound does not        exceed 100 μg per g of iron.

E43. The iron complex compound of any one of E24-E42, wherein the ironcomplex compound is an iron carbohydrate complex compound.

E44. The iron complex compound of E43, wherein the content of reducingaldehyde groups in the carbohydrate that serves as ligand in the ironcomplex compound has been reduced by

-   -   oxidation,    -   hydrogenation, or    -   a combination of both.

E45. The iron complex compound of E43, wherein the iron carbohydratecomplex compound is selected from iron carboxymaltose, iron polyglucosesorbitol carboxymethyl ether complex, iron mannitol complex, irondextran, iron hydrogenated dextran, iron oxidized dextran, ironcarboxyalkylated reduced oligo- and polysaccharides, iron sucrose, irongluconate, iron dextrin, iron hydrogenated dextrin, iron oxidizeddextrin, iron polymaltose, iron hydrogenated polymaltose, ironpolyisomaltose, iron hydrogenated polyisomaltose, iron hydrogenatedoligosaccharides such as iron hydrogenated oligoisomaltose, ironhydroxyethyl starch, iron sorbitol, iron dextran glucoheptonic acid anda mixture of two or more thereof.

E46. The iron complex compound of E43, wherein the iron carbohydratecomplex compound is selected from iron carboxymaltose, iron polyglucosesorbitol carboxymethyl ether complex, iron mannitol complex, irondextran, iron hydrogenated dextran, iron sucrose, iron gluconate, irondextrin, iron hydrogenated oligoisomaltose and a mixture of two or morethereof.

E47. The iron complex compound of any one of E43-E46, wherein thecarbohydrate component of the iron carbohydrate complex compound has aweight average molecular weight (M_(W)) of from 500 to 80,000 Da.

E48. The iron complex compound of any one of E43-E47, wherein theapparent molecular weight of the iron carbohydrate complex compound isin the range of from 800 to 800.000 Da.

E49. The iron complex compound of any one of E24-E42, wherein the ironcomplex compound is a polymeric ligand-substituted oxo-hydroxy ironcomplex compound.

E50. The iron complex compound of E49, wherein the polymericligand-substituted oxo-hydroxy iron complex compound is obtained by

-   -   (1) contacting an iron preparation with the ligand in an aqueous        solution at a first pH(A); and    -   (2) changing the pH(A) to a second pH(B) to cause a solid        precipitation of the polymeric ligand-substituted oxo-hydroxy        iron complex compound.

E51. The iron complex compound of E49 or E50, wherein the ligand isselected from a carboxylic acid, such as adipic acid, glutaric acid,tartaric acid, malic acid, succinic acid, aspartic acid, pimelic acid,citric acid, gluconic acid, lactic acid and benzoic acid; a foodadditive such as maltol, ethyl maltol and vanillin; an anion with ligandproperties such as bicarbonate, sulphate and phosphate; a mineral ligandsuch as silicate, borate, molybdate and selenate; an amino acid such astryptophan, glutamine, proline, valine and histidine; and anutrient-based ligand such as folate, ascorbate, pyridoxine and niacin;and a mixture of two or more thereof.

E52. The iron complex compound of any one of E24-E51, wherein the ironcomplex compound is stabilized with a compound selected from citricacid, a citrate and a gluconate.

E53. The iron complex compound of any one of E24-E52 having the formula{FeO_((1-3X))(OH)_((1+3X))(C₆H₅O₇ ³⁻)_(X)}, (C₆H₁₀O₆)_(R)(—-C₆H₁₀O₅⁻)_(Z)(C₆H₁₃O₅)_(R), (MeCl)_(Y) that contains H₂O,

-   -   wherein    -   X is 0.0311±0.0062, R is 0.1400±0.0420, Z is 0.4900±0.1470, Y is        1.8000±1.0800, and Me is a monovalent metal ion.

E54. The iron complex compound of E53, wherein X is 0.0311±0.0031, R is0.1400±0.0210, Z is 0.4900±0.0735, Y is 1.8000±0.4500.

E55. A composition comprising the iron complex compound of any one ofE24 and a pharmaceutically acceptable carrier.

E56. The iron complex compound of any one of E24-E54 or the compositionof E55 for therapeutic use.

E57. The iron complex compound of any one of E24-E54 for use intreatment or prophylaxis of iron-deficiency in a subject.

E58. The iron complex compound for the use according to E57, wherein thesubject is a non-human animal and the iron complex compound is selectedfrom iron dextran, iron hydrogenated dextran and iron dextranglucoheptonic acid.

E59. The iron complex compound for the use according to E57, wherein thesubject is a human suffering from lost or impaired kidney function, forexample a human in need of dialysis.

E60. The iron complex compound for the use according to any one ofE57-E59, wherein the subject is an infant.

E61. The iron material for the use according to E57 or E58, wherein thesubject is a pregnant mammal or a mammal expected to become pregnant ora nursing mammal.

E62. The iron complex compound for the use according to any one ofE57-E61, wherein the subject is selected from human, pig, horse, dog,cat, camel, sheep, goat and cow.

E63. The iron complex compound for the use according to any one ofE57-E62, wherein the treatment or prophylaxis comprises parenteraladministration of the iron complex compound.

E64. The iron complex compound for the use according to E63, wherein theparenteral administration is selected from intramuscular injection,subcutaneous injection, intravenous injection and intravenous infusion,and optionally is a bolus injection or infusion.

E65. The iron complex compound for the use according to any one ofE57-E64, wherein the treatment or prophylaxis comprises theadministration of a dose of the iron complex compound containing anamount of 200 mg or more iron within 2 minutes or less.

E66. The iron complex compound for the use according to any one ofE57-E65, wherein the treatment or prophylaxis comprises theadministration of one dose of iron complex compound containing an amountof 200 mg or more iron every four weeks or more frequently, for exampleevery three weeks or more frequently, every three weeks or morefrequently, or every week or more frequently.

E67. The iron complex compound for the use according to any one ofE57-E66, wherein the treatment or prophylaxis comprises theadministration of a single dose of iron complex compound containing anamount of 500 mg to 1000 mg iron.

E68. The iron complex compound for the use according to any one ofE57-E66, wherein the treatment or prophylaxis comprises theadministration of an amount of iron complex compound containing 15-20 mgiron per kg bodyweight of the subject in one sitting.

EXAMPLES Example 1: Production of Ferric Chloride from Carbonyl Iron

Ferric Chloride was produced from carbonyl iron using a three stepreaction in a nitrogen atmosphere.

Step 1: Carbonyl iron (5.2 kmol) was reacted with a slight excess of HCl(10.8 kmol) so as to form ferrous chloride and hydrogen.

The reaction in this step follows the equation: Fe+2 HCl→FeCl₂+H₂

Step 2: The ferrous chloride obtained in step 1 was reacted with HCl(4.06 kmol) and a slight deficit of NaClO₃ (0.82 kmol) so as to formferric chloride, sodium chloride and water.

The reaction in this step follows the equation:

6 FeCl₂+6 HCl+NaClO₃→6 FeCl₃+NaCl+3 H₂O

Step 3: Residual ferrous chloride remaining after step 2 was convertedto ferric chloride by controlled oxidation achieved by step-wiseaddition of hydrogen peroxide until no more ferrous iron was detected.

The main reaction in this step follows the equation:

FeCl₂+2 HCl+H₂O₂→FeCl₃+2 H₂O

There is a side reaction of hydrochloric acid and hydrogen peroxidefollowing the equation: 2 HCl+H₂O₂→Cl₂+2 H₂O

Example 2: Production of Iron Complex Compounds from Carbonyl Iron

Iron isomaltoside 1000, an iron hydrogenated oligoisomaltose(oligoisomaltoside) complex compound, was produced using the processdescribed in WO 2010/108493 A1.

FeCl₃ produced from carbonyl iron by the process described in example 1was used. An amount of FeCl₃ containing 240 kg Fe³⁺ was combined with560 kg of a hydrogenated oligoisomaltose (oligoisomaltoside, i.e.isomaltoside 1000) preparation having a weight average molecular weightof 1,097 Da and a content of mono- and disaccharides of 0.8 wt-%. Thisproduced 903 kg iron isomaltoside 1000 powder containing 24.2 wt-% Fe³⁺.Thus about 91.1% Fe³⁺ was incorporated into the final product that hadthe formula {FeO_((1-3X))(OH)_((1+3X))(C₆H₅O₇ ³⁻)_(X)}, (H₂O)_(T),(C₆H₁₀O₆)_(R)(—C₆H₁₀O₅—)_(Z)(C₆H₁₃O₅)_(R), (NaCl)_(Y) with X being about0.031, T being about 0.25, R being about 0.14, Z being about 0.49 and Ybeing about 0.14.

Example 3: Production of Iron Complex Compounds from Ferric ChlorideDerived by Extracting an Aqueous Iron Salt from an Aqueous Solution fromNickel Ore Using an Organic Solvent

In a first step, a ferric chloride preparation was produced by providingan aqueous ferric chloride solution that was obtained during theprocessing of an iron-containing nickel ore for nickel production andextracting the aqueous ferric chloride solution using an organicsolvent.

In a second step, iron isomaltoside 1000, an iron hydrogenatedoligoisomaltoside complex compound, was produced using the processdescribed in WO 2010/108493 A1.

An amount of the FeCl₃ obtained in the first step containing 240 kg Fe³⁺was combined with 560 kg of a hydrogenated oligoisomaltoside preparationhaving a weight average molecular weight of 1,022 Da and a content ofmono- and disaccharides of 1.2 wt-%. This produced 888 kg ironhydrogenated oligoisomaltoside powder containing 24.8 wt-% Fe³⁺. Thusabout 91.8% Fe³⁺ was incorporated into the final product that had theformula {FeO_((1-3X))(OH)_((1+3X))(C₆H₅O₇ ³⁻)_(X)}, (H₂O)_(T),(C₆H₁₀O₆)_(R)(—C₆H₁₀O₅—)_(Z)(C₆H₁₃O₅)_(R), (NaCl)_(Y) with X being about0.031, T being about 0.25, R being about 0.14, Z being about 0.49 and Ybeing about 0.14.

Example 4: Non-Iron Metal Impurity Contents of Iron Complex Compounds

The amounts of non-iron metals in several iron complex compounds of theinvention determined by ICP-MS are summarized in Table 1.

TABLE 1 Non-iron metal impurity contents of iron complex compounds Ironcomplex compound prepared from Non-iron impurity content [μg per g iron]Ligand Iron preparation Al Cr As Cd Hg Pb Low molecular ferric chloridepreparation  9.7  1.4 0.1 <0.001* <0.02* <0.003* weight dextran ^(#)according to example 1 Low molecular ferric chloride prepared by  9.319.5 0.2   0.1 <0.02*   0.1 weight dextran^(#) extracting an aqueousiron salt solution obtained during the processing of an iron- containingore with an organic solvent hydrogenated ferric chloride prepared by 6.6  1.1 0.3   0.3 <0.02*   0.0 dextran^(##) extracting an aqueous ironsalt solution obtained during the processing of an iron- containing orewith an organic solvent iron isomaltoside 1000 according to example 2 6.3 10.7 1.2 <0.001* <0.02*   0.2 iron isomaltoside 1000 according toexample 3 10.6  1.3 0.1   0.1 <0.02*   0.0 *limit of detection^(#)resulting iron dextran complex compound in accordance with BritishPharmacopoeia monograph for Iron Dextran Injection ^(##)weight averagemolecular weight (Mw) in the range of from 2,000 to 6,000 Da

1-15. (canceled)
 16. A process for preparing an iron carbohydratecomplex compound comprising the steps of (i) obtaining an ironpreparation by a. decomposing iron pentacarbonyl; b. recrystallizationof an iron salt from an aqueous solution thereof c. extracting anaqueous iron salt solution with an organic solvent and recovering theiron salt by stripping the organic solvent; d. precipitation at an anodeduring electrolysis of an aqueous iron salt solution; e. contacting anaqueous iron salt solution with a base so as to form a precipitate ofiron hydroxide and separating the precipitate from the liquid byfiltration or centrifugation; or f. distillation of ferric chloride froma mixture comprising ferric chloride and non-volatile impurities,wherein the iron preparation comprises iron in a form selected from awater-soluble iron salt, an iron hydroxide or an iron oxide-hydroxide,the amount of arsenic in the iron preparation does not exceed 4.5 μg perg of iron, and the amount of lead in the iron preparation does notexceed 1.5 μg per g of iron; and (ii) reacting the iron preparation witha ligand in the presence of water so as to form the iron carbohydratecomplex compound, and (iii) recovering said iron carbohydrate complexcompound.
 17. The process of claim 16, wherein recrystallization in step(i)(b) is recrystallization of ferric nitrate from an aqueous solutioncontaining nitric acid.
 18. The process of claim 16, wherein the aqueousiron salt solution of step (i)(c) is obtained during the processing ofan iron-containing nickel ore.
 19. The process of claim 16, wherein theorganic solvent is an alcohol having about 4-20 carbon atoms or anorganic solutions of an amine salt.
 20. The process of claim 16, whereinthe aqueous solution in step (i)(d) comprises iron chloride or ironsulfate.
 21. The process of claim 16, wherein the base in step (i)(e) isselected from sodium hydroxide and sodium carbonate.
 22. The process ofclaim 16, wherein step (ii) comprises heating said iron preparation andligand in the presence of water to boiling.
 23. The process of claim 16,wherein the amount of iron in the iron carbohydrate complex compound,determined for dry matter, is from 10 to 50 wt-%.
 24. The process ofclaim 16, further comprising (iv) formulating said iron carbohydratecomplex compound for parenteral administration.
 25. The process of claim24, wherein the concentration of iron in the formulation is from 25 to300 mg/ml.
 26. The process of claim 25, wherein said formulation is forsubcutaneous injection, intramuscular injection, intravenous injection,or intravenous infusion.
 27. The process of claim 16, wherein the amountof cadmium in the iron preparation does not exceed 0.6 μg per g of iron,and the amount of mercury in the iron preparation does not exceed 0.9 μgper g of iron.
 28. The process of claim 16, wherein the amount ofchromium in the iron preparation does not exceed 330 μg per g of iron.29. The process of claim 16, wherein the amount of aluminum in the ironpreparation does not exceed 200 μg per g of iron.
 30. The process ofclaim 16, wherein the amount of arsenic in the iron complex compounddoes not exceed 1.5 μg per g of iron; the amount of lead in the ironcomplex compound does not exceed 0.5 μg per g of iron; the amount ofcadmium in the iron complex compound does not exceed 0.4 μg per g ofiron; the amount of mercury in the iron complex compound does not exceed0.3 μg per g of iron; the amount of chromium in the iron complexcompound does not exceed 100 μg per g of iron; and/or the amount ofaluminum in the iron complex compound does not exceed 25 μg per g ofiron.
 31. The process of claim 16, wherein the iron carbohydrate complexcompound is selected from iron carboxymaltose, iron polyglucose sorbitolcarboxymethyl ether complex, iron dextran, iron hydrogenated dextran,iron sucrose, iron gluconate, iron polymaltose, iron hydrogenatedoligosaccharides such as iron hydrogenated oligoisomaltose, ironhydroxyethyl starch, iron dextran glucoheptonic acid and a mixture oftwo or more thereof.
 32. The process of claim 31, wherein said ironcarbohydrate complex compound is iron hydrogenated oligoisomaltose. 33.The process of claim 31, wherein said iron carbohydrate complex compoundis iron dextran or iron hydrogenated dextran.
 34. The process of claim31, wherein said iron carbohydrate complex compound is ironcarboxymaltose.
 35. An iron carbohydrate complex compound, wherein theamount of arsenic in the iron complex compound does not exceed 4.5 μgper g iron, and the amount of lead in the iron complex compound does notexceed 1.5 μg per g iron.
 36. The iron carbohydrate complex compound ofclaim 35, wherein the amount of cadmium in the iron complex compounddoes not exceed 0.6 μg per g of iron, and the amount of mercury in theiron complex compound does not exceed 0.9 μg per g of iron.
 37. The ironcarbohydrate complex compound of claim 35 or claim 36, wherein theamount of chromium in the iron complex compound does not exceed 330 μgper g of iron.
 38. The iron carbohydrate complex compound of claim 35,36, or 37, wherein the amount of aluminum in the iron complex compounddoes not exceed 200 μg per g iron.
 39. The iron carbohydrate complexcompound of claim 35, wherein the amount of arsenic in the iron complexcompound does not exceed 1.5 μg per g of iron; the amount of lead in theiron complex compound does not exceed 0.5 μg per g of iron; the amountof cadmium in the iron complex compound does not exceed 0.4 μg per g ofiron; the amount of mercury in the iron complex compound does not exceed0.3 μg per g of iron; the amount of chromium in the iron complexcompound does not exceed 100 μg per g of iron; and/or the amount ofaluminum in the iron complex compound does not exceed 25 μg per g ofiron.
 40. The iron carbohydrate complex compound of claim 35 or 39,wherein the iron carbohydrate complex compound is selected from ironcarboxymaltose, iron polyglucose sorbitol carboxymethyl ether complex,iron dextran, iron hydrogenated dextran, iron sucrose, iron gluconate,iron polymaltose, iron hydrogenated oligosaccharides such as ironhydrogenated oligoisomaltose, iron hydroxyethyl starch, iron dextranglucoheptonic acid and a mixture of two or more thereof.
 41. The ironcarbohydrate complex compound of claim 35 or 39, which is ironhydrogenated oligoisomaltose.
 42. The iron carbohydrate complex compoundof claim 41, wherein said iron hydrogenated oligoisomaltose has theformula: {FeO_((1-3X))(OH)_((1+3X))(C₆H₅O₇ ³⁻)_(X)}, (H₂O)_(T),(C₆H₁₀O₆)_(R)(—C₆H₁₀O₅—)_(Z)(C₆H₁₃O₅)_(R), (NaCl)_(Y) wherein X is about0.031, T is about 0.25, R is about 0.14, Z is about 0.49, and Y is about0.14.
 43. The iron carbohydrate complex compound of claim 41, whereinthe iron hydrogenated oligoisomaltose is ferric derisomaltose.
 44. Theiron carbohydrate complex compound of claim 35 or 39, which is irondextran or iron hydrogenated dextran.
 45. The iron carbohydrate complexcompound of claim 35 or 39, which is iron carboxymaltose.
 46. The ironcarbohydrate complex compound of claim 35 or 39, wherein the amount ofiron in the iron carbohydrate complex compound, determined for drymatter, is from 10 to 50 wt-%.
 47. The iron carbohydrate complexcompound of claim 35 or 39, which is formulated for parenteraladministration.
 48. The iron carbohydrate complex compound of claim 47,wherein the concentration of iron in the formulation is from 25 to 300mg/ml.
 49. The iron carbohydrate complex compound of claim 48, whereinsaid formulation is for subcutaneous injection, intramuscular injection,intravenous injection, or intravenous infusion.